Persons with acquired immunodeficiency syndrome (AIDS) have a higher incidence of invasive pneumococcal disease (IPD) than other adults, and many receive long-term trimethoprim-sulfamethoxazole (TMP-SMZ) prophylactic therapy. We used 1998-1999 data from the Active Bacterial Core surveillance of the Emerging Infections Program Network to compare IPD infections between adults aged 18-64 years with human immunodeficiency virus (HIV) infection and other adults. Of 2346 patients with IPD, 416 (18%) had HIV or AIDS (HIV/AIDS). Certain serotypes (serotypes 6A, 6B, 9N, 9V, 18C, 19A, 19F, and 23F) were more common among patients with HIV/AIDS than in adults with no underlying disease (P<.05, vs. serotype 4), even when TMP-SMZ-nonsusceptible isolates were excluded. HIV/AIDS (adjusted odds ratio [aOR], 1.93; 95% confidence interval [CI], 1.44-2.59), immunocompromising conditions other than HIV/AIDS (aOR, 1.56; 95% CI, 1.12-2.18), and black race (aOR, 1.50; 95% CI, 1.20-1.88) were independent risk factors for infection with these serotypes. HIV/AIDS was not an independent risk factor for TMP-SMZ nonsusceptibility. Vulnerability to certain serotypes among adults with HIV/AIDS may have implications in prevention strategies.